Search Results (415)

This study aimed to clarify whether interleukin-1 receptor antagonist (IL-1RA) mediates the age-dependent immunomodulatory capacity of adipose-derived stem cells (ASCs) via regulating macrophage polarization. ASCs from young (Y-ASCs) and aged (O-ASCs) C57BL/6 mice were isolated. IL-1RA, which was identified as an age-sensitive candidate through integrated transcriptomic and proteomic screening in our prior publication, was validated by qPCR, immunofluorescence, and ELISA. RAW264.7 macrophages were polarized and co-cultured with ASCs or treated with recombinant IL-1RA; IL-1RA in Y-ASCs was silenced by siRNA (82.3 ± 5.1% knockdown efficiency). The results showed Y-ASCs had 2.1-fold higher IL-1RA mRNA and significantly higher protein secretion than O-ASCs (p < 0.001). Y-ASC transplantation enhanced M2 polarization (CD206⁺ cells increased from 9.36% to 21.4% in vivo; p < 0.01) in aged mouse adipose tissue and reduced inflammation (serum IL-1β lowered by 42.3 ± 5.1%; p < 0.001), while O-ASCs had no effect. Recombinant IL-1RA recapitulated Y-ASC effects (M2 macrophages increased from 0.92% to 61.8%; p < 0.001), and IL-1RA silencing abrogated Y-ASC function. The data indicate IL-1RA is a key age-sensitive mediator of ASC immunomodulation. Declined IL-1RA may contribute to impaired aged ASC efficacy, highlighting donor age’s importance. This provides mechanistic insights and guides IL-1RA-targeted optimization for ASC therapies in age-related inflammatory disorders. Full article

The prevalence of obesity among elderly women is increasing, particularly in postmenopausal populations. This exploratory study investigated the associations between chondroitin sulfate (CS) supplementation and body weight control in ovariectomized (OVX) rats, a preclinical model for postmenopausal physiology. CS supplementation was associated with significantly reduced body weight gain and preserved adipocyte morphology. CS-treated OVX rats exhibited decreased gut microbiota diversity, with reduced abundance of Photobacterium and Rhodococcus and increased abundance of Turicibacter. Metabolomic analysis revealed elevated levels of carbohydrates, fatty acids, and their conjugates, some of which correlated with body weight parameters. Bioinformatic analysis identified enriched KEGG pathways including tyrosine metabolism, glucosinolate biosynthesis and thiamine metabolism. Collectively, these findings provide preliminary correlational evidence in an OVX rat model supporting the potential of CS as a food supplement for body weight control, although causal relationships and clinical applicability warrant further investigation in postmenopausal populations. Full article

Ischemic stroke remains a leading cause of death and long-term disability worldwide. Although acute reperfusion therapies have improved outcomes in selected patients, effective strategies that directly promote neurovascular repair during the subacute and chronic phases remain limited. Vascular network remodeling in the peri-infarct region is increasingly recognized as a key process supporting tissue repair, blood–brain barrier restoration, and functional recovery after stroke. Microglia, as resident immune cells of the central nervous system, undergo dynamic morphological, metabolic, and functional changes after ischemic injury and participate in inflammation, phagocytic clearance, blood–brain barrier regulation, and tissue repair. Among repair-associated microglial states, microglia with M2d-like features have attracted increasing attention because of their potential association with immunoregulation and pro-vascular repair. However, whether repair-associated microglia with M2d-like features represent a distinct and stable microglial subtype after stroke remains unresolved. In this review, we summarize current evidence linking repair-associated microglial responses to vascular network remodeling after ischemic stroke, with particular emphasis on the conceptual value of the M2d-like state. We discuss putative mechanisms involving paracrine signaling, perivascular localization, metabolic reprogramming, and extracellular vesicle-mediated communication. We also evaluate therapeutic implications, including traditional Chinese medicine, extracellular vesicle-based strategies, and nanodelivery systems. However, current therapeutic evidence does not establish that these interventions specifically induce M2d-like microglial states. We highlight the need for rigorous validation of cellular identity, spatial localization, and functional vascular outcomes. Overall, the M2d-like framework provides a candidate perspective for understanding immune–vascular coupling after stroke, but further studies integrating single-cell omics, spatial mapping, lineage tracing, and functional vascular assessment are required to define the identity and functional contribution of repair-associated microglia with M2d-like features. Method: This article is a narrative review. The relevant literature was searched in PubMed from database inception to June 2026 using combinations of the terms “ischemic stroke,” “microglia,” “macrophage,” “vascular remodeling,” “angiogenesis,” “M2d,” “extracellular vesicles,” “traditional Chinese medicine,” and “nanomedicine.” Priority was given to original studies directly examining microglial or myeloid responses and vascular repair after ischemic stroke. Relevant review articles were included to provide conceptual background. Because direct evidence for M2d-like microglial responses after stroke remains limited, selected studies involving peripheral macrophages, tumor-associated macrophages, traditional Chinese medicine, extracellular vesicles, and nanomedicine were included as indirect or hypothesis-generating evidence. Evidence was interpreted according to the disease model, cellular source, and vascular outcomes examined, with stroke-specific microglial studies regarded as more directly relevant than evidence extrapolated from non-stroke or non-microglial models. Full article

Inflammation and oxidative stress induced by high glucose levels constitute essential factors impeding wound healing in diabetes, posing a significant threat to public health. Despite its notable anti-inflammatory and antioxidant potential, the clinical applicability of quercetin is hampered by its hydrophobicity and limited oral bioavailability. To address these issues, the thin-film hydration method was used to encapsulate quercetin into FQ micelles. Subsequently, 3-aminophenylboronic acid-modified oxidized alginate was crosslinked with polyvinyl alcohol, and simultaneously loaded with glucose oxidase (GOX) and FQ micelles, to construct a glucose-activated cascade acidification-triggered controlled-release hydrogel (OSSP@FQ&GOX). The phenylboronic ester bonds in the hydrogel are responsive to glucose and undergo cleavage. GOX-mediated oxidation of glucose produces gluconic acid, resulting in a lower local pH and subsequently triggering FQ micelle release. The released FQ micelles alleviate oxidative stress and exert immunomodulatory effects, while the hydrogel also provides self-healing, and biocompatible properties that facilitate cutaneous regeneration in diabetic mice. Thus, this study highlights the potential of combining GOX with natural products and multi-stimuli-responsive hydrogels for the treatment of chronic diabetic wounds, while also opening new avenues for the development of multifunctional wound dressings. Full article

The escalating prevalence of bacterial infections has intensified the search for innovative antimicrobial strategies, particularly for infected wound management. Chondroitin sulfate (CS), a naturally occurring glycosaminoglycan with established biocompatibility, presents an attractive scaffold for developing metal ion-functionalized biomaterials. This study reports the fabrication of chondroitin sulfate–copper complex (CSCu) and chondroitin sulfate–zinc complex (CSZn) through an ion exchange method, wherein Cu²⁺ and Zn²⁺ ions bind to the groups of carboxylate, sulfate, or N-acetyl from the CS backbone. The resulting complexes exhibited copper or zinc loading capacities of about 6.6% and demonstrated potent antibacterial activity against E. coli and S. aureus. The integration of CSCu or CSZn with sodium alginate yielded a hydrogel system with a higher apparent viscosity, possessing injectability and spreadability on the skin surface and a porous three-dimensional internal structure conducive to wound healing applications. In a murine model of S. aureus-infected full-thickness wounds, topical application of CSCu and CSZn hydrogels substantially accelerated wound closure, achieving 97.46% and 98.11% healing, respectively, by day 10. Additionally, treatment with CSCu or CSZn hydrogels significantly attenuated systemic inflammatory responses, as reflected in lowered serum TNF-α, IL-1β, and IL-6 alongside increased IL-10. Histological evaluation confirmed enhanced re-epithelialization and stratum spinosum formation in treated wounds. These findings establish CSCu and CSZn as a promising bioactive agent for addressing bacterial wound infections through a dual mechanism of direct antibacterial action and immunomodulatory effects, offering a valuable alternative to conventional antibiotic therapies. Full article

Imiquimod-induced skin inflammation is the most widely used psoriasis mouse model. Although p38 mitogen-activated protein kinase reportedly plays a role in the pathogenesis of psoriatic inflammation, the purpose of one of its upstream activators, apoptosis signal-regulating kinase 1 (ASK1), remains unclear. This study investigated the role of ASK1 and its molecular mechanism in the imiquimod-induced psoriasis model. Compared to wild-type mice, the ASK1 knockout (KO) mouse skin lesion showed a higher clinical score and a thicker epidermis. The mRNA expression of pro-inflammatory cytokines, such as IL-17 and TNF-α, was also higher. Notably, the expression of aryl hydrocarbon receptor (AhR), a sensor for xenobiotic chemicals that is expressed in the skin to strengthen the skin barrier and accelerate terminal differentiation of the epidermis—as well as its downstream molecule CYP1A1, but not NRF2—was increased in the ASK1 KO psoriatic skin lesion. Immunoprecipitation analysis, followed by Western blotting, revealed that ASK1 interacts with AhR in cells transfected with their respective expression vectors, potentially leading to reduced AhR expression. These results suggest that ASK1 negatively regulates the development of the imiquimod-induced mouse psoriasis model by interacting with AhR and presumably antagonizing the AhR-CYP1A1 axis. Full article

The genus Naegleria comprises free-living amoebae characterized as amphizoic and ubiquitous microorganisms. Naegleria fowleri is the only species pathogenic to humans, causing primary amebic meningoencephalitis. The 26S proteasome represents the principal catalytic complex responsible for the degradation and recycling of intracellular proteins in eukaryotic cells. This complex consists of the 20S and 19S proteasome subunits, with the latter involved in the recognition and processing of ubiquitinated proteins and their delivery to the degradation site. Although the 26S proteasome has been characterized in various pathogenic protozoa, only the 20S proteasome has been studied within the genus Naegleria. The objective of this study was to demonstrate the presence of 19S subunits in N. fowleri. Bioinformatics analyses were employed to evaluate the presence and homology of non-ATPase subunits (Rpn10, Rpn11, and Rpn13) and ATPase subunits (Rpt2, Rpt3, and Rpt5). Additionally, the presence, localization, and correlation of 19S proteasome proteins with the 20S proteasome were assessed using experimental approaches. The results indicate that N. fowleri possesses proteins corresponding to the 19S proteasome, which, together with the 20S core particle, contribute to the formation of the 26S proteasome. Full article

Background: Intrauterine adhesions, a leading cause of female infertility, frequently recur in 30–62.5% of patients despite hysteroscopic adhesiolysis and adjuvant therapies. Current intrauterine barriers, including injectable hydrogels, often lack sufficient bioactivity and tissue retention, failing to address the underlying pathological inflammation and oxidative stress driving abnormal fibrosis. Methods: Herein, we tailored a reactive oxygen species (ROS)-responsive, mussel-inspired adhesive injectable hydrogel (OHA-CP@TA) to intelligently modulate the inflammatory niche and promote normal endometrial regeneration. OHA-CP@TA was fabricated through Schiff base bonds between oxidized hyaluronic acid (OHA) and phenylboronic acid-modified carboxymethyl chitosan (CMCS-PBA), and boronate ester bonds between CMCS-PBA and tannic acid (TA). Results: OHA-CP@TA exhibited good mechanical strength, injectability, self-healing, and shear-thinning properties, and importantly, robust and stable adhesion to uterine tissue, overcoming endometrial mucus clearance. It also showed favorable in vivo uterine cavity retention for at least 7 days that covered the critical endometrial repair period. Within the postoperative inflammatory milieu, OHA-CP@TA intelligently released TA in a ROS-dependent manner, which effectively scavenged various ROS and significantly alleviated inflammation, and promoted M1 macrophage polarization into M2 phenotype. This targeted ROS scavenging and immunoregulation inhibited endometrium fibrosis progression, evidenced by downregulation of α-SMA and Col-1, and actively promoted endometrial repair and regeneration, demonstrated by enhanced angiogenesis, increased endometrial thickness, and restoration of glandular numbers. Furthermore, OHA-CP@TA exhibited good biocompatibility, in vivo biodegradability and safety. Conclusions: Therefore, OHA-CP@TA represents a promising, clinically translatable strategy for overcoming the limitations of current IUA management. Full article

Antimicrobial resistance in Mycoplasma gallisepticum (MG), a primary causative agent of chronic respiratory disease in poultry, has reached alarming levels, underscoring the urgent need for alternative strategies. Natural products have emerged as promising candidates owing to their multi-target mechanisms of action. This review synthesizes current evidence on natural anti-MG agents, critically appraising their in vitro and in vivo efficacy, molecular mechanisms, and translational potential. A mechanistic taxonomy is proposed for distinguishing direct pathogen-directed mechanisms (membrane disruption, adhesion inhibition, virulence factor neutralization) from indirect host-directed mechanisms, notably NF-κB/MAPK pathway modulation and gut–lung axis immunoregulation. Emphasis is placed on anti-infective polypharmacology, exemplified by luteolin’s dual inhibition of the TatD virulence factor and host inflammatory cascades. The gut–lung axis represents a novel therapeutic frontier, with Bacillus subtilis KC1 controlling respiratory mycoplasmosis through intestinal microbiome remodeling and systemic AhR activation. Despite encouraging efficacy data, critical knowledge gaps persist, including a scarcity of rigorous in vivo trials under commercial conditions, incomplete mechanistic characterization, and challenges in standardizing complex natural product formulations. Natural products are best positioned not as wholesale antibiotic replacements but as integral components of integrated, antibiotic-sparing strategies aligned with antimicrobial stewardship and One Health principles. Full article

Pregnancy modulates the function of the thyroid gland to facilitate maternal immune tolerance, and nuclear factor kappa B (NF-κB) subunits, the IκB family, and toll-like receptors (TLRs) and complement signaling pathways may be implicated in maternal thyroid immunoregulation. However, it is unclear whether early pregnancy modulates the expression of NF-κB subunits, the IκB family, TLRs, and complement components in the maternal thyroid. The objective of this study was to analyze the effects of early pregnancy on the expression of genes and proteins of these signaling pathways in the maternal thyroid in ewes. In this study, ovine thyroids (n = 6 for each group) were sampled on day 16 of the estrous cycle (N16) and on days 13, 16, and 25 of pregnancy (P13, P16, and P25) with one conceptus. The ewes had an average weight of 41 kg and a body condition score of 3. The mRNA and protein expression of the NF-κB subunits and IκB family were analyzed by RT-qPCR, western blot, and immunohistochemistry. The results showed that the expression of all NF-κB subunits, the IκB family, and TLRs, as well as C1q, C1r, C2, C4a, C5b, and C9, peaked at P16 among these four stages (p < 0.05). In addition, C1s expression was greater at N16 and P16 than at P13 and P25 (p < 0.05), and C3 expression was stronger at P16 and P25 compared to N16 and P13 (p < 0.05). In conclusion, early pregnancy modulates the expression of NF-κB subunits, the IκB family, TLRs, and complement components in the ovine thyroid at both the mRNA and protein levels, which may be essential for maternal thyroid adaptation to pregnancy and beneficial for the prevention of pregnancy-related thyroid diseases in ewes. Full article

Glatiramer acetate (GA) is a first-line disease-modifying therapy for multiple sclerosis (MS) with well-established moderate efficacy and high safety, yet its mechanisms of action remain incompletely understood. DNA methylation plays a significant role in MS development and is modulated by various environmental factors, including therapeutic drugs. In this pilot study, we report the first prospective analysis of genome-wide DNA methylation changes in peripheral blood mononuclear cells (PBMCs) from four female relapsing-remitting MS patients before GA initiation and after approximately four and eight months of therapy. We identified 365 loci that are characterized by differential methylation, distinguishing post-treatment time points from baseline, with significant enrichment in CpG islands, shores, and promoter regions. Two distinct temporal patterns emerged: (1) non-monotonic DNA methylation changes peaking at four months and associated with response to foreign antigenic stimuli, and monotonic changes progressively increasing by eight months and related to mTOR-associated pathways relevant to chronic inflammation and neurodegeneration. Integration of DNA methylation and transcriptomic data revealed significant methylation-expression correlations for eight genes, including HLA-DMA, PDE4A, and SMOX—genes with established roles in MS-associated antigen presentation, immunoregulation, and neuroinflammation. Cell composition of PBMCs remained stable throughout treatment. In general, GA therapy for MS appears to induce dynamic, locus-specific DNA methylation changes in PBMCs, with distinct temporal patterns suggesting a biphasic response of the immune system. However, given that none of the individual DMPs reached genome-wide significance, the results presented in this pilot study strongly require validation in larger independent cohorts. Nevertheless, we believe that our findings provide insights into the immunomodulatory effects of GA and lay the foundation for future hypothesis-driven studies to develop epigenetic biomarkers for therapeutic monitoring and generic GA product assessment. Full article

Background: Oral squamous cell carcinoma (OSCC) remains a clinically challenging malignancy characterized by aggressive behavior and limited therapeutic options. Bitter taste receptors (TAS2Rs), expressed across multiple tissues and cancer types, have recently emerged as regulators of tumor biology and immune responses; however, their functional significance in OSCC remains poorly understood. Methods: Immunohistochemical analysis was performed using surgically resected human tongue OSCC specimens and a tissue microarray (TMA) cohort. In parallel, four TAS2R agonists were evaluated in SCC7 cells to assess intracellular calcium responses. RNA sequencing was conducted to analyze transcriptional changes following diphenidol treatment, and functional assays, including proliferation, migration, and apoptosis analyses, were performed in vitro. Antitumor effects were further evaluated in a syngeneic SCC7 mouse model, followed by TUNEL staining and flow cytometry to assess apoptosis and immune cell infiltration. Results: TAS2R38 expression was markedly upregulated in dysplastic and invasive OSCC lesions with predominant nuclear localization and was associated with histological grade and clinical stage, indicating an early and sustained alteration during tumor progression. Among the agonists tested, diphenidol most strongly induced IP₃-dependent intracellular Ca²⁺ elevation. RNA sequencing revealed upregulation of Il1rl1 and Lzts2. Functionally, diphenidol significantly suppressed SCC7 cell proliferation and migration and induced apoptosis in vitro. In vivo, diphenidol reduced tumor volume and weight and increased apoptotic activity. Flow cytometry demonstrated a marked reduction in tumor-infiltrating CD4⁺CD25⁺Foxp3⁺ regulatory T cells, indicating modulation of the tumor immune microenvironment. Conclusions: TAS2R activation by diphenidol suppresses tumor growth through both tumor-intrinsic mechanisms and modulation of the tumor immune microenvironment in OSCC. These findings define TAS2R-mediated calcium signaling as a novel axis linking tumor progression and immunoregulation. Given that diphenidol is a clinically approved drug with an established safety profile, our results provide a strong rationale for TAS2R-targeted drug repurposing strategies in cancer therapy. Full article

As stem cell therapy in regenerative medicine becomes more socially accepted, human perinatal tissue is attracting attention as a source because it can be harvested non-invasively. Human placental extracts (HPEs), which are prepared using acid hydrolysis and autoclaving, have been approved for treating menopausal disorders and liver dysfunction. This study investigated a new HPE formulation prepared under milder conditions by omitting acid hydrolysis and autoclaving to improve its effectiveness. The new HPE contains relatively high-molecular-weight proteins, including high levels of thioredoxin-1, as well as primarily extracellular matrix proteins such as thrombospondin-1. These proteins appear to be intact or partially fragmented, but they can still potentially maintain their domain structure. The HPE showed both antioxidant and neurite outgrowth activities in a neuronal cell line SH-SY5Y. In a mouse model of hair graying caused by X-ray irradiation, multiple administration of the HPE significantly reduced it. Additionally, the HPE, but not heat-inactivated HPE, alleviated the mechanical allodynia in a mouse model with chemotherapy-induced peripheral neuropathy. Due to the fact that HPE can be produced non-invasively in large quantities in a short time without the need for culturing, the new HPE may have the potential to be an effective and feasible therapy via multiple mechanisms. Full article

As natural nanoscale intercellular messengers, exosomes exhibit considerable potential in modulating inflammation, angiogenesis, immunoregulation, and tissue remodeling, making them attractive candidates for regenerative medicine. However, their clinical translation remains limited by rapid systemic clearance, nonspecific biodistribution, insufficient lesion retention, and functional attenuation in hostile pathological microenvironments. In this review, we propose that biomaterial engineering should evolve from providing passive exosome carriers to constructing active regulatory platforms capable of precise spatiotemporal control. We summarize engineering strategies along two complementary dimensions. In the temporal dimension, biomaterials can enable sustained, sequential, or microenvironment-responsive release to match the dynamic phases of tissue repair. In the spatial dimension, biomaterials can improve local retention, tissue anchoring, structural guidance, endogenous cell recruitment, and lesion-specific delivery. Using cutaneous wound healing, osteochondral regeneration, myocardial repair, and neural regeneration as representative examples, we further analyze these strategies through a “clinical challenge–engineering strategy–biological mechanism” framework, with particular attention to how engineered systems influence key signaling pathways such as PI3K/Akt, Wnt/β-catenin, NF-κB, and PTEN/PI3K/Akt/mTOR. We also discuss translational barriers, including exosome heterogeneity, safety concerns inherited from parental cells, large-scale GMP-compliant manufacturing, product standardization, storage stability, and regulatory classification of exosome–biomaterial hybrids. Finally, we highlight emerging directions, including multi-mechanism combinational systems, closed-loop responsive platforms, and artificial intelligence-assisted design for personalized exosome therapeutics. This review provides a design-oriented framework to accelerate the bench-to-bedside development of biomaterial-enabled precision exosome therapy. Full article

Dickkopf-1 (DKK1) is a 266-amino-acid secreted glycoprotein originally identified as a high-affinity antagonist of the canonical Wnt/β-catenin signaling pathway and has emerged as a complex regulator in oncology. While historically considered as a tumor suppressor due to its ability to abrogate Wnt-driven proliferation, recent discoveries highlight a paradoxical pro-oncogenic role across various malignancies. The molecular mechanisms by which DKK1 promotes tumor progression, metastasis, and immune evasion are driven by its interaction with cell-surface receptors, specifically LRP5/6 and CKAP4. The DKK1-CKAP4 axis independently activates PI3K/AKT signaling, facilitating epithelial–mesenchymal transition (EMT), chemoresistance, and the formation of osteolytic bone lesions. Furthermore, DKK1 serves as a critical orchestrator of the tumor microenvironment (TME) by driving comprehensive immune reprogramming. It mediates the recruitment of myeloid-derived suppressor cells (MDSCs) and inactivates cytotoxic CD8⁺ T cells and natural killer (NK) cells, thereby fostering an immunosuppressive tumor microenvironment and resistance to checkpoint inhibitors. Interestingly, cancer-associated fibroblasts (CAFs) are a primary source of DKK1 in the stroma, where they facilitate immune evasion. Clinically, elevated circulating DKK1 levels correlate with advanced disease stages, increased metastatic potential, and poor overall survival in solid and hematological tumors. When used in combination with established biomarkers, serum DKK1 levels demonstrate significant utility for early detection and therapeutic monitoring. Given its intricate impact on malignancy, DKK1 has become a promising therapeutic target, with ongoing clinical trials investigating neutralizing antibodies such as DKN-01 to disrupt its oncogenic and immunosuppressive signaling. Understanding the context-dependent nature of DKK1 signaling remains essential for refining its application as both a biomarker and a component of emerging precision immunotherapy strategies. By prioritizing the literature from the last decade, this review characterizes DKK1 as a key mediator of tumor progression and immune reprogramming, while assessing its clinical potential as a biomarker and therapeutic target. Full article